Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Anesthesiology, Nanhai Hospital of Southern Medical University, Foshan 528000, P.R. China.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

An itchy pair of channels

Chronic itching is a serious condition and is often resistant to antihistamines. Kim and colleagues explored the channels in sensory neurons that mediate the response to itch-inducing stimuli, in particular the inflammatory mediator histamine and the antimalarial drug chloroquine, both of which activate distinct G protein–coupled receptors (GPCRs) at the cell surface. Although TRPV1 and TRPA1, two members of the transient receptor potential (TRP) family of calcium channels, have been implicated in histamine- and chloroquine-induced itching, the authors found that a third member of this family, TRPV4, was also important. Sensory neurons with both TRPV4 and TRPV1 responded to both histamine and chloroquine. Additionally, TRPV4 interacted with TRPV1, enhancing TRPV4 activity. Their data decode itch perception and suggest that targeting TRPV1 or TRPV4 may be beneficial in treating intractable chronic itch.

Abstract

The transient receptor potential channels (TRPs) respond to chemical irritants and temperature. TRPV1 responds to the itch-inducing endogenous signal histamine, and TRPA1 responds to the itch-inducing chemical chloroquine. We showed that, in sensory neurons, TRPV4 is important for both chloroquine- and histamine-induced itch and that TRPV1 has a role in chloroquine-induced itch. Chloroquine-induced scratching was reduced in mice in which TRPV1 was knocked down or pharmacologically inhibited. Both TRPV4 and TRPV1 were present in some sensory neurons. Pharmacological blockade of either TRPV4 or TRPV1 significantly attenuated the Ca2+ response of sensory neurons exposed to histamine or chloroquine. Knockout of Trpv1 impaired Ca2+ responses and reduced scratching behavior evoked by a TRPV4 agonist, whereas knockout of Trpv4 did not alter TRPV1-mediated capsaicin responses. Electrophysiological analysis of human embryonic kidney (HEK) 293 cells coexpressing TRPV4 and TRPV1 revealed that the presence of both channels enhanced the activation kinetics of TRPV4 but not of TRPV1. Biochemical and biophysical studies suggested a close proximity between TRPV4 and TRPV1 in dorsal root ganglion neurons and in cultured cells. Thus, our studies identified TRPV4 as a channel that contributes to both histamine- and chloroquine-induced itch and indicated that the function of TRPV4 in itch signaling involves TRPV1-mediated facilitation. TRP facilitation through the formation of heteromeric complexes could be a prevalent mechanism by which the vast array of somatosensory information is encoded in sensory neurons.